Gels formed by crosslinking polysaccharides bearing pendant carboxylate groups have been known and used for many years in the areas of dental health care and food preparation technologies. Of these gels, the most commonly encountered are composed of water-insoluble alginates which include, with the exception of magnesium and the alkali metal salts, the group II metal salts of alginic acid. These water-insoluble alginate gels are typically formed by the chemical conversion of water-soluble alginates, in an aqueous solution, into water-insoluble alginates. This conversion usually is accomplished by the reaction of a water-soluble alginate with polyvalent cations released from a soluble di- or trivalent metal salt. The water-soluble alginates include the ammonium, magnesium, potassium, sodium, and other alkali metal salts of alginic acid.
The most common of the alginate gels is composed of calcium aliginate. Sources for the crosslinking calcium ions used in the formation of these gels generally include calcium carbonate, calcium sulfate, calcium chloride, calcium phosphate, and calcium tartrate.
Controlling the time of gelatin has traditionally been an integral part of conventional methods of preparing these calcium alginate gels and is usually accomplished by regulating the concentration of free calcium ions in the solution. Typically the concentration of free calcium ions is controlled by manipulation of the ionization rate of the calcium salt and/or by the inclusion of other compounds in the solution which react with the free calcium ions.
Conventional processes regulate the rate of ionization by selecting a calcium salt having the desired solubility and/or by adjusting the pH of the solution to increase the solubility of the calcium salt. The solubility of slightly soluble or water-insoluble calcium salts can be increased by lowering the pH of the solution. Generally the pH is lowered by the addition of an acid or by the addition of a substance such as an acid lactone that hydrolyzes to an acid. Commonly used pH adjusters include glucono-delta-lactone and acids such as acetic, adipic, citric, fumaric, lactic and tartaric acid.
The availability of calcium ions can also be controlled by the addition of gel retarders. Known gel retarders are salts having an ion that forms a water-insoluble or slightly water-soluble bond to the calcium ions. The retarder competes with the water-soluble alginate for the free calcium ions thereby depriving the alginate of some of the crosslinking ions and delaying gelatin. Common retarders are the alkali metal phosphates, oxalates and citrates.
Conventional methods for preparing these water-insoluble calcium alginate gels typically involve adding solid water-soluble alginate and solid calcium salt to an aqueous medium as disclosed in U.S. Pat. No. 3,455,701, and U.K. Patent Specification No. 1,579,324, published Nov. 19, 1980, or adding a solution or dispersion of calcium salt to an aqueous solution of water-soluble alginate as disclosed in U.S. Pat. Nos. 2,756,874, 4,381,947 and 4,401,456. Typically these methods include the addition of gel retarders and/or pH adjusters to provide control over the rate of gelatin.
Traditionally, water-insoluble alginate gels have been used extensively in dental impression materials and as thickening or setting agents in food preparations. Recently, however, water-insoluble alginate gels have found utility as a form-in-place wound dressing material as disclosed in Swedish Patent Application Publication No. 424,956, published Aug. 23, 1982. This dressing is prepared by mixing water-soluble alginate, a soluble metal salt having metal ions that react with the water-soluble alginate to form a crosslinked water-insoluble alginate, and water to form a reactive cream-like paste that is spread over the wound surface. After application to the wound surface the constant progression of the crosslinking reaction transforms the cream-like paste into an elastic rubber-like composition.
Likewise, German Patent Application No. 3601132 (published July 23, 1987), discloses an alginate which gels in situ and is useful for protecting the mucosa and delivering disinfectants or pharmaceutically active agents. The composition consists of at least two components capable of forming a gel on mixing, such as a calcium salt and alginic acid, polyglucuronic acid, polymanuronic acid, propylene glycol alginic acid, polygalacturonic acid, polyarabinic acid, their salts or esters, pectin, gum arabic and their mixtures, to be simultaneously or sequentially placed onto the mucous membrane.
Alginate gels have also been used to provide sustained release of drugs. Stockwell, et al., in "In Vitro Evaluation of Alginate Gel Systems as Sustained Release Drug Delivery Systems", Journal of Controlled Release, Volume 3, pp. 167-175 (1986), disclose gelatin capsules containing a powdered mixture of sodium alginate, calcium phosphate, sodium bicarbonate, lactose and a drug (chlorpheniramine, sodium salicylate or caffeine). In situ in the stomach the gelatin capsule dissolves, hydration and gelatin of the alginate and crosslinking by calcium occur to provide a gel barrier at the surface, and the sodium bicarbonate effervesces, releasing carbon dioxide which becomes entrapped in the gel network.
Another sustained release device is disclosed in U.S. Pat. No. 4,613,497. Anhydrous tablets, capsules, powders or suppositories are made from a mixture of water soluble polysaccharide gum, a biocompatible gelling salt, an effervescent base, a water soluble biocompatible acid or acid salt and a pharmaceuticaly active material. These compositions find use in gastrically active compositions and vaginal contraceptives.
Furthermore, German Patent No. 368,694 discloses a foaming dental adhesive made from an adhesive material, such as alginic acid or sodium alginate, at least one carbonate and/or hydrogen carbonate and at least one organic, water-soluble salt or a water-soluble acid salt of a polyboric acid. The later two components form CO.sub.2 in an aqueous environment and stimulate foaming of the adhesive.
Medical uses for these gels brings with it new concerns with regard to the purity and sterility of the polysaccharide gel being formed. For example, it is generally desirable that retarders and suspending agents which leave residual deposits in the gel network not be present in the gel forming components used to form foamed polysaccharide hydrogels for medical uses Furthermore, to be effective in preventing contamination and infection, it is generally desirable that the hydrogel forming materials be sterile prior to their application.
Theoretically, a sterile form-in-place polysaccharide hydrogel may be prepared by either (1) sterilizing the gel-forming components separately prior to mixing and maintaining the components in a sterile environment before, during and after mixing until the composite material is used, or (2) mixing the gel-forming components together first and then sterilizing the composite material immediately prior to use. The latter alternative, however, has little practical utility as it requires each batch to be individually sterilized prior to use, and thereby places unacceptable demands upon the time and facilities of the health care professional. Likewise, in order for the former alternative to be useful, sterile gel-forming components, and a method of mixing these components while maintaining them in a sterile environment, must be available to the health care professional.
Thus, there is a need in the medical arts for a foam-in-place polysaccharide hydrogel which can be easily provided in a sterile form. Additionally, it is desirable for the gel-forming components to mix easily and quickly so as to minimize the demands on the health care professional's time and energy. It is further desirable to provide a foam forming mechanism which coordinates the rate of gel formation with the rate of foam formation, so as to assure uniform dispersal of foam within the gelled polysaccharide structure. Only in this way can a dimensionally stable foamed polysaccharide hydrogel be produced.
Heretofore it has been unknown to employ polysaccharide hydrogels as preoperative preparations. There exists a need for an effective form-in-place surgical preparation, particularly one well suited for vaginal or rectal surgery. Nosocomial infections are more common after vaginal or rectal surgery largely because the surgical techniques are done through an already contaminated field. Attempts to reduce infections have been made using prophylactic antibiotics, (Ledger WJ, Sweet RI, Headington JT: "Prophylactic Cephaloridine in the Prevention of Post-Operative Infection in Premenopausal Women Undergoing Vaginal Hysterectomy." Am. J. Obstet Gynecol. 1973:115-766), various preoperative preparations (Telinde R: Operative Gynecology. Philadelphia, JB Lippincott Co., 1962, p.8.), different surgical techniques (Richardson AC, Lyon JB, Graham EE: "Abdominal Hysterectomy: Relationship Between Mortality and Surgical Technique." Am. J. Obstet. Gynecol. 115:953-961 (1973)), and specific drainage systems (Swartz WH, Tanaree P: "T-tube Suction Drainage and/or Prophylactic Antibiotics: Randomized Study of 451 Hysterectomies". Obstet Gynecol. 47:665-670 (1976)) with no significant decrease.
Because none of these methods has been successful in decreasing infection following vaginal and/or rectal surgical procedures, there remains a need for a surgical preparation that 1) is capable of releasing antimicrobial in a prolonged manner for up to 24 hours or more; 2) swells to the shape of the cavity into which it is injected, thus delivering antimicrobial to a large surface area; 3) forms a stable, biocompatible, water-insoluble gel that will absorb exudates with very little swelling; and 4) can be easily removed from the body cavity as a complete unit.